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Environ Pollut. 2019 Jan;244:534-548. doi: 10.1016/j.envpol.2018.10.034. Epub 2018 Oct 10.

Sodium fluoride induced skeletal muscle changes: Degradation of proteins and signaling mechanism.

Author information

1
Stem Cells and Regenerative Medicine Centre, Yenepoya Research Centre, Yenepoya Deemed to be University, University Road, Mangalore, 575018, Karnataka, India. Electronic address: shenoy@yenepoya.edu.in.
2
Stem Cells and Regenerative Medicine Centre, Yenepoya Research Centre, Yenepoya Deemed to be University, University Road, Mangalore, 575018, Karnataka, India.
3
College of Medicine, University of Sharjah, United Arab Emirates.
4
Department of Oral Biology & Genomic Studies, A.B.Shetty Memorial Institute of Dental Sciences, Nitte University, Mangalore, 575018, Karnataka, India; School of Health and Life Sciences, Biomedical and Environmental Health Group, De Montfort University, Leicester, United Kingdom.
5
Stem Cells and Regenerative Medicine Centre, Yenepoya Research Centre, Yenepoya Deemed to be University, University Road, Mangalore, 575018, Karnataka, India. Electronic address: Bipasha.bose@yenepoya.edu.in.

Abstract

Fluoride is a well-known compound for its usefulness in healing dental caries. Similarly, fluoride is also known for its toxicity to various tissues in animals and humans. It causes skeletal fluorosis leading to osteoporosis of the bones. We hypothesized that when bones are affected by fluoride, the skeletal muscles are also likely to be affected by underlying molecular events involving myogenic differentiation. Murine myoblasts C2C12 were cultured in differentiation media with or without NaF (1 ppm-5 ppm) for four days. The effects of NaF on myoblasts and myotubes when exposed to low (1.5 ppm) and high concentration (5 ppm) were assessed based on the proliferation, alteration in gene expression, ROS production, and production of inflammatory cytokines. Changes based on morphology, multinucleated myotube formation, expression of MyHC1 and signaling pathways were also investigated. Concentrations of NaF tested had no effects on cell viability. NaF at low concentration (1.5 ppm) caused myoblast proliferation and when subjected to myogenic differentiation it induced hypertrophy of the myotubes by activating the IGF-1/AKT pathway. NaF at higher concentration (5 ppm), significantly inhibited myotube formation, increased skeletal muscle catabolism, generated reactive oxygen species (ROS) and inflammatory cytokines (TNF-α and IL-6) in C2C12 cells. NaF also enhanced the production of muscle atrophy-related genes, myostatin, and atrogin-1. The data suggest that NaF at low concentration can be used as muscle enhancing factor (hypertrophy), and at higher concentration, it accelerates skeletal muscle atrophy by activating the ubiquitin-proteosome pathway.

KEYWORDS:

Atrophy; C2C12; Differentiation; Hypertrophy; Myoblasts; Myotubes; Parts per million (ppm); Sodium fluoride (NaF)

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